During the 1950's and 1960's many pharmaceutical concerns launched extensive programs to synthesize modified corticosteroids. The objective was to create systemically active compounds having more potent antiflammatory activity than the naturally occuring corticoids but without correspondingly elevated levels of side effects such as interference with the pituitary-adrenal relationship (leading to adrenal insufficiency) and effects on electrolyte balance and glucose metabolism.
The initial efforts resulted in certain quite potent compounds of the prednisolone series having a 9.alpha.fluoro constituent in combination with 16-methyl or 16.alpha.hydroxy substitution, such as Betamethasone, dexamethasone, and triamcinolone. Certain compounds having 16.alpha.-methyl substitution along with a 6.alpha.fluoro constituent (paramethasone) or with combined 6.alpha., 9.alpha.fluoro substitution (flumethasone) also proved interesting.
In all these compounds the problem of electrolyte imbalance (primarily sodium retention with potassium depletion) was substantially reduced. Various theories were advanced for this, with one or more groups being said to enhance potency (.DELTA.' and 9.alpha.F) with (9.alpha.F) or without (.DELTA.') some degree of potentiation of mineralcorticoid activity and with other substituents (16-OH, .alpha.CH.sub.3 or .beta.CH.sub.3) being said to attenuate somewhat the mineralcorticoid effect. In any event, when the lower doses made possible by enhanced potency were used, observed electrolyte activity was reduced and it is generally accepted today that at therapeutic doses the compounds which are .DELTA.'.sup.4 dienes with 6' and/or 9.alpha. halogen substitution combined with 16- methyl or 16.alpha.hydroxy substitution do not cause an unacceptable degree of electrolyte imbalance.
Despite these early successes, significant separation of other side effects from therapeutic activity proved difficult, although it was later noted that in some cases the 16.alpha.methyl substitution did by itself augment anti-inflammatory activity somewhat more than glycogen deposition and that the 16.beta.methyl substitution diminished glycogenic properties somewhat without altering the anti-inflammatory activity. Thus, these compounds are still widely used today in various forms: Tablets and syrups for normal systemic application (Betamethasone, Dexamethasone, and Triamcinolone), suspensions for long acting systemic or parenteral applications (Betamethasone acetate, Paramethasone acetate and Triamcinolone diacetate), and creams or aerosols for topical application (Betamethasone and Dexamethasone)
In the mid-1960's, attention turned to attempts at development of highly effective topical corticoids with little or no systemic effects. The former objective was pursued through a combination of potentiated anti-inflammatory activity per se and/or improved absorption through the stratum corneum. The latter objective was pursued through reduction of systemic activity per se and/or reduction in the ability to migrate from the epidermis into the dermis after penetration of the stratum corneum.
The two primary corticoids developed at that time which are still major factors today are the 16-17 acetonides of Triamcinolone and its 6.alpha., 9.alpha. diflorocounterpart, fluocinolone. For some reason, still not fully understood, tramcinolone acetonide is about ten times as active as triamcinolone topically, but only equiactive systemically. Flucinolone acetonide is essentially ineffective systemically even though it is perhaps even more active topically than its triamcinolone counterpart. For topical steroids these compounds plus related Fluandrenalone (6.alpha.F, 16.alpha.OH, hydrocortisone 17,21 acetonide) today represent more than one half of all prescriptions in the United States.
At the end of the 1960's, much attention was given to the esters of the above discussed compounds and of other compounds, such as beclomethasone (the resulting dipropionate), which had not found earlier commerical use. In some, but by no means all instances, the esterification at 17 and/or 21 was found to improve the potency of therapeutic effect as evaluated by Vasoconstriction assays. What is most striking from the literature of that time is the unpredictability of the results of esterification when trying to apply knowledge gained with one skeletal series to another skeletal series. Mostly this is due to the subtle alteration of the shapes of molecules caused by even minor structural differences and it is on the basis of shape that hormones are recognized by their receptors.
One of the most completely explored series of esters is those of Betamethasone (9.alpha.F, 16.beta.-CH.sub.3). When esterified in the 17 position, betamethasone is potentiated from activity of 1% of fluocinalone acetonide to up to 350% of fluocinolone acetonide as the ester chain increases from acetate through butyrate and propionate up to valerate, the latter compound being one of the most widely used topical anti-inflammatory agents today. The 17-benzoate, U.S. Pat. No. 3,529,060, has recently been found to be of equal activity to the valerate. Esterification in the 21-position also causes some potentiation of anti-inflammatory activity, but primarily imparts more long acting effects as was expected, from early findings, mentioned previously, on the 21-acetates of betamethasone. The esters of Betamethasone today represent almost one-third of prescriptions for topical steroids in the United States.
Another series receiving a lot of attention were the 6,9 difluoroprednisolones through the work of Gardi, et al described for example in the Journal of Medicinal Chemistry, 15, 556 (1972) and 15,783 (1972), in Steroids, 16:6, 663 (1970), and in U.S. Pat. Nos. 3,780,177 (6,9 difluoroprednisolone 17-butyrale, 21-acylates), 3,784,692 (the corresponding 17 propionates, 21 acylates), 3,691,214 (17-valerates) and 3,857,941 (17-benzoates). Commercial uses of these compounds has not yet begun in the United States.
Finally, the diacetate of 6,9 difluoro-16methyl-prednisolone was discovered by Upjohn to be a very interesting compound-one subsequently commercialized in the United States. However, none of the other esters appear to have received attention.
An excellent summary of the history of structural modifications of corticosteroids appears as Chapter 9, Anti-inflammatory Steroids, in Anti-Inflammatory Agents, Scheerer (Ed), Academic Press (1974).
Despite the work over a decade ago with the 6,9 difluoroprednisolones esters, the 6,9 difluoro 16 methyl prednisolone, 17,21 diacetate and despite the even earlier work with the betamethasone (9.alpha.fluoro, 16.beta.-CH.sub.3 prednisolone) esters and the Beclomethasone (9.alpha.chloro, 16.beta.-CH.sub.3 prednisolone) esters, surprisingly the only literature reference describing the 9.alpha.Cl, 6.alpha.F 16 methylated prednisolone or its esters appears to be the mention of 16.beta.methyl diacetate as an intermediate in Belgian Pat. No. 858709 (1978) for the production of certain 9,11 halogenated steroids.
I have now discovered that while the 16.alpha.methyl series produce unacceptable impact on the adrenal and thymus, the 16.beta.methyl series are important anti-inflammatory agents in the cotton pellet granuloma rat assay and the modified McKensie vasoconstriction assay in man, and are exhibiting only limited effect on the thymus and adrenal glands.